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To stem the ever-growing threat of antimicrobial resistance (AMR), our research focuses on non-antibiotic strategies to combat multi-drug resistant (MDR) pathogens. We have developed up to the preclinical stage an inhibitor, 3A11, which is the first targeting copper-transporting P-type ATPase protein CopA. It limits the growth of several Gram-positive pathogens, such as Staphylococcus aureus , Enterococcus faecalis , Enterococcus faecium , and the two most common MDR strains causing nosocomial infections: methicillin-resistant S. aureus and vancomycin-resistant enterococci. We will collect sequenced clinical isolates from the vast bacterial repositories of our project partners to test the bactericidal potential of 3A11.The inclusion of clinical isolates with different phenotypes and genetic lineages will guide our investigations of the underlying molecular mechanisms of action. This will be further studied using transcriptomic analysis to determine changes in the global expression profiles of the isolates induced by 3A11. As part of the preclinical development, we will investigate the potential development of resistance to 3A11 by determining the mutation rates in the bacteria and further characterizing the ensuing phenotypes, genotypes, and fitness cost. Lastly, we will gauge the efficacy of 3A11 in cell-lines like, human keratinocytes (HaCaT), primary keratinocytes, human macrophage cells (THP-1), and in murine models to investigate 3A11´s role in bacterial pathogenesis.